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Totally Synthetic by Paul H. Docherty, 4 May 2009

Total Synthesis of Acutumine


F. Li, S. S. Tartakoff, S. L. Castle, J. Am. Chem. Soc. 2009, 131, 6674-6675.

DOI: 10.1021/ja9024403

Acutumine is a complex target with five contiguous stereocenters, two quaternary carbon centers and chlorine bound to the congested carbon skeleton. Castle  mentions selective T-cell cytotoxicty, and anti-amnesic effects.

Much of the initial chemistry is published in a paper in Org. Lett., 2007, so we now focus on an advanced step: One interesting reaction is the chlorination of the allylic alcohol. Castle performs an invertive displacement, citing Robert Williams. Cleary the allylic nature of the alcohol makes all the difference.

A radical 5-exo-trig cyclisation/polar crossover is key to the construction of the cyclopentane. The use of an oxaziridine results in oxidation with fantastic control of stereochemistry in a very good yield.

A few futher steps are explained in the publication in JACS. The creaction of the final ring required first an allylation. Substrate control was unfortunately unsuccessful, resulting at best in a 7:3 d.r. However, using a large excess of Nakamura’s chiral allylzinc reagent gave them a far better yield. However, the new allyl group is in the wrong position, which can be corrected in an oxy-Cope rearrangement, that creates the second quaternary center without problems in good yield including a transfer of the asymmetry.

For the construction of the final ring, a methylamine derivative is required,  that performs a 1,4-addition in the presence of a Lewis acid into that remarkably stable dimethyl ketal in a moderate yield, installing the final stereocenter in predictably cis manner.

Nice total synthesis! I’m looking forward to more from the Castle group!